Summary Long-lasting changes at synapses enable memory storage in the brain. Although aging is associated with impaired memory formation, it is not known whether the synaptic underpinnings of memory storage differ with age. Using a training schedule that results in the same behavioral memory formation in young and aged mice, we examined synapse ultrastructure and molecular signaling in the hippocampus after contextual fear conditioning. Only in young, but not old mice, contextual fear memory formation was associated with synaptic changes that characterize well-known, long-term potentiation, a strengthening of existing synapses with one input. Instead, old-age memory was correlated with generation of multi-innervated dendritic spines (MISs), which are predominantly two-input synapses formed by the attraction of an additional excitatory, presynaptic terminal onto an existing synapse. Accordingly, a blocker used to inhibit MIS generation impaired contextual fear memory only in old mice. Our results reveal how the synaptic basis of hippocampal memory storage changes with age and suggest that these distinct memory-storing mechanisms may explain impaired updating in old age.
Graphical Abstract
Highlights • Aged mice form contextual memory like young mice, but reconsolidation is impaired • Only in young mice is contextual memory formation associated with structural LTP • In aged mice, contextual memory formation correlates with multi-innervated spines • Inhibition of multi-innervated spines impairs memory in aged but not young mice
Aziz et al. show that the synaptic basis of contextual fear memory differs dramatically with age. In young mice, memory associates with strengthening of synapses with one synaptic input, whereas in aged mice it correlates with multi-input synapses. Memory updating in old mice is impaired, and this may be due to the distinct memory-storing mechanism.